Intracellular calcium is an important factor which induces various physiological responses such as neuronal excitement, muscle contraction, hormone secretion, fertilization, immune response, cell motility, and cell death. The concentration of intracellular calcium is regulated by means of ion channels or pumps, such as voltage-dependent calcium channels and receptor-operated calcium channels. Voltage-dependent calcium channel is a calcium channel that is opened and closed depending on the change in the potential difference between inside and outside of a cell, and exist on the cellular membranes of muscle cells or nerve cells. The voltage-dependent calcium channels are currently classified into L-type, T-type, N-type, P/Q-type and R-type calcium channels, based on electrophysiological characteristics and pharmacological characteristics. Unlike the L-type, N-type, P/Q-type and R-type calcium channels that are classified as medium potential- and high potential-activated calcium channels in view of the membrane potential activation threshold, the T-type calcium channels are activated at a potential close to the resting membrane potential. Therefore, the T-type calcium channels are considered to function as a trigger for an influx of calcium into the cell, and to participate in the pacemaker activity, production of low-threshold calcium spikes, and burst firing.
T-type calcium channels include three subtypes, i.e. Cav3.1 (α1G), Cav3.2 (α1H) and Cav3.3 (α1I), and expression of the channels in, for example, the brain, nerve tissues, heart, kidneys, liver, pancreas, smooth muscles and testicles, has been reported. It has been suggested that T-type calcium channels are responsible for physiological functions such as the pacemaker function of the heart, renovascular tonus, hormone secretion, nerve firing and pain transmission, and activation of the T-type calcium channels relates to the onset and progress of various pathological conditions such as hypertension, tachyarrhythmia including atrial fibrillation, cardiac hypertrophy, cardiac failure, renal dysfunction, pain, epilepsy, sleep disorder, obesity, and cancers. Therefore, T-type calcium channel antagonist is believed to be an effective drug for the treatment or prevention of these diseases (Non Patent Documents 1 to 16).
Known examples of the T-type calcium channel antagonists include efonidipine and mibefradil, as well as 3,4-dihydroquinazoline derivatives disclosed in Patent Document 1, quinazoline derivatives disclosed in Patent Document 2, pyridylamide derivatives disclosed in Patent Document 3, indole derivatives disclosed in Patent Document 4, thiazole derivatives disclosed in Patent Documents 5 and 6, aisoxazole derivatives disclosed in Patent Document 7, and imidazopyridine derivatives disclosed in Patent Document 8.
Furthermore, regarding T-type calcium channel antagonists having a nitrogen-containing non-aromatic ring as a common mother nucleus, Patent Document 9 discloses N-piperidinylacetamide derivativeS, Patent Documents 10 and 11 disclose 3-fluoropiperidine derivatives, Patent Document 12 discloses imidazoylmethylpiperidine derivatives, Patent Document 13 discloses piperazine derivatives, and Patent Document 14 discloses oxopiperazine derivatives, as the T-type calcium channel antagonists.